Certain pyridyl acylamides

ABSTRACT

THE COMPOUNDS ARE OF THE CLASS OF UNSATURATED FATTY ACID PYRIDYL AMIDES WHICH POSSESS ANTIVIRAL AND TUMOR GROWTH INHIBITING PROPERTIES, ILLUSTRATIVE EXAMPLES OF SUCH COMPOUNDS ARE N-(5-METHYL-2-PYRIDYL)-LINOLAMIDE AND N-(5-METHYL-2-PYRIDYL)-LINOLENAMIDE.

'1 13,822,276; 1 CERTAIN PYRIDYL A'CYLAMIDES' Alex Meisels, Base], andEmilio Schott, Riehen, Switzerland, assignors to Ciba-Geigy Corporation,Ardsley,

.Y. No Drawing. Application June 9,'1'969,'-Ser. No."834,596,

now Patent No. 3,555,035, which is a continuation of application Ser.No. 610,804, Jan. 23, 1967, which in turn is a continuation-in-partoi;',application Ser. No. 474,167, July 22, 1965, both now abandoned.Divided and this application Sept. 3, 1970, Ser. No. 69,428

a 'Claims priority, application Switzerland, July 31,1964,

, 10,068/64; July 2, 1965, 9,322/65 U f The portion of the term of thepatent subsequent to Feb. 2, 1999, has been disclaimed Int. Cl. C07d31/44 US. Cl. 260-295 AM ABSTRACT on THE DISCLOSURE The compounds are ofthe class of unsaturate'd' 'fatty acid pyridyl amides which possessantiviral and tumor growth inhibiting properties. Illustrative examplesof such United States Patent Ofii A 3,822,276 Patented July 2, 1974 Thetumor growth-inhibiting activity of thez comj pounds falling underFormula I, including those in which R is iodo, was determined in animaltests on subcutaneous or oral administration in cases of transplantedEhr- .lich carcinoma, sarcoma induced by methylcholanthrene (Mcsarcoma), skin vcarcinoma induced by dimethylbenzanthracene (DMBAcarcinoma) in the rnouse and of sp ontaneous mammary carcinoma. Thesetests were performed using five animals per dosage and ten as controls.'Ihe'active ingredients were administered in the case of Ehrlichcarcinoma on four, and in cases of induced and spontaneous tumors oneight consecutive days in dosages which were at most% or A,respectively, of'the Dosis tolerata maxima (Dtm.)'. The size of theEhrlich carcinoma was determined on the sixth, that of the in- H ducedtumors on the first day after conclusion of the test by measuring thecross section and that of the spontaneous mammarycarcinoma twenty daysafter the first application.

The tumorgrowth-inhibitingetfect of compounds of Formula I wasdetermined by comparing the reduced dicompounds areN-(S-methyl-Z-pyridyl)-linolamide and N- (S-methyl-Z-pyridyl-linolenamide,

DETAILED DISCLOSURE This invention relates to new amides of unsaturatedfatty acids as well as processes for their production.

mula

acid or of a-linolenic acid, and R2 represents, in p-position to theamide group, bromo, iodo, lower alkyl,]ower alkoxy, lower alkenyloxy,lower alkylthio, lower alkenylthio, lower alkanoylamino, lower'akoxycarbo'nyl, or carbamyl. e v

The termslower alkyl, andderivations thereofusing the root al'k embracehydrocarbon chains having one through three carbon atoms. I

A preferred subclass of compounds are thbsecompounds of Formula Iwherein R -CO is in the 2- or 3-position of the pyridine ring andrepresents the acyl radical of-linoleic acid. 2 1.

v A third preferred subclass of compounds are those compounds of-Formula I wherein R CO-- is in the 2-posi- Particularly, the inventionconcerns amides of the forwherein R CO represents theacyl radical oflinoleic ameter and/or the weight of the tumors in the test anim l w tthose n th r l and sse r s e i pe cent.

A representative number of the compounds of the invention were found tobe significantly active in these tests; Unexpectedly they were moreactive than the unsubstitutedrparent substance N-(2-pyridyl)-linolamide, which compound is known and was described by F.Zetzsche Ber., 7l, 15164521 (1938).

. l Table I lists the results obtained with the particularly enhanced bythe favorableratiobetween-the significantly active and the maximaltolerated dosages. i v

As antiviral agents, especially, in the treatment of infections withHerpes, simplex virus there are useful those compounds falling underFormula I in which the pyridyl ring bearsbromo or iodo, as substituent Ractive compounds of the invention and of the known compound.

TABLE! Inhibition ottumor Y Type 0! Dosage in growth in Compound testedtumor mgJkg. percent:

N-(5-methyl-2-pyridylJ- Ehrlich 4X1, 250 8.0. ca. 25

linolamide. Carcinoma. 4x625 s.c.v ea. 25

4X312.5 s.e. ca. 25

4X1,250 p.o. ca. 25

. s 4x625 p.o. 7 11-25 MC Sarcoma..- 8X625 s.e. 51-75 DMBA Car- 8x625ac. ca. 75

einoma. 8X312.5 so. on. 50

8X312.5 p.o. 75-99 Spont.mam- 8x625 5.0. 11-25 maryCa. 8X3L25 s.c. 11-50v N-(6-methoxy-3-pyridyl)- DMBACar- 8X625 s.e. 26-50 linolamide. cinoma.

N-(6-aeet lamino-3- DMBA Car- 8x625 5.0. 75-99 pyridyl -lino1amide.cinema. 8x625 p.o. 11-25 v 8x312 p.o. 51-99 N-(6-methyhnercapto-3- MCSarcoma.- 8x625 so. 26-50 pyrldyl)-linolamide.

N-(G-allylmercapto-Zi- Spont.mam- 8x625 -s.c. 26-50 pyridyD-llnolamide.mary 0a.

N-(S-carbamyl-Z-pyrldyD- Spont.mam- 10X312 s.c. 51-75 linolamide. i maryCa. N-5(ethoxy'earbonyl-2- Mo Sarcoma; 10X625 p.o 25-50pyridyD-linolarmde. I 10X312 p.o. 26-50 DMBA Car- 10X625 5.0. 021.99einoma. 10X312 5.0. 26-80 10X156 5.0. 75-90 8x625 p.o. ca. 99

8x312 p.o. 26-50 8x250 p.o. 51-75 8x156 p.o. 75-99 Spont.mam- 10X5005.0. 62-50 mary Ca.

8x500 p.o 51-75 8X250 p.0 ca. 50

The maximal tolerated dose as determined in mice with one singlesubcutaneous administration and'an observation period of 10 days ishigher than 5000 mg./kg. for each test compound described in Table I.

The antiviral activity of the compound of Formula I wherein R is bromoor iodo is demonstrated in mice of the albino strain Swiss. Five animalsare used per dosage and at least twice the amount are usedv as controls. .The active compounds are administered subcutaneously or orally assolution in sesame oil, on four consecutive days. The firstadministration is given 30 min. before" infection with the LD of aHerpes simplex virus/HO preparation. 1

The prolongation of the mean survivaltirne of the-test group in percentof the controls is a criterion for elfectiveness.

representative compounds.

The maximal tolerated dose determined in mice by one single subcutaneousadministration and an observation TABfiE-F-Continued V V. 14V, I 7... V.'i".'.. ,n of tumor Typeiot Dosage in growth in Compound tested tumormg./kg. percent N-(fi-methoxjcarbonyl-Z- DMBA Car- 110x625 5.0. 1. 7 5175 pyridyl)-linolamide.- cinoma. 10X625 'p.o. 26'i5 Spont.mam- 10 625s.c. 75:99 mary Ca. 10X250 s.c. 51-75 10X500 5.0. 26-50 10x250 p.().11-25 -N-J(-isopro oxycarbonyk DMBA'Cur- X625 5.0. 75-09Z-pyridyl-lmolamide. cinoma. s

=-N-(5-methyl-2-pyridyl)- Ehrlich Car '4X1,250 s.c." 11 ..1inolenamido.vcinoma. 4X1,250,,.p.o. 26-50 p 4 e2 5 p. o. 1 1-25 1 MO Sarcoma.. 81,250,p.o. 51-75 8x625 p.o. 26- 50 ,Nv( 5iodo-2i-pyridyl)- .MGSarcoma.-. 8x625 s.e. I 26-50 linolenamide. I 8x625 p.o. 11-25 DMBA cansxozs e. 26- 50 cinema. 8x625 p.o. ca. 50 8x312 p.o. 26-50NKZ-pyridyD-linolaniide Ehrlich Car- 4X1, L250 s.c. 0 (known compound).""clnoma. 4X1,2 50- p.0. 0

MC Sarcoma 8x625 s.c. ca. 25 8x625 p.05 08.15

. DMB A Car- 8X625"s.c. ca. 15 cinema 8x625 p.o.'

Table 2 shows the activity of various osage 'or two period of 10 days ishigher than 5000 mg.-/kg. for both test compounds described in Table 2.The new amides of Formula I are produced-by reacting an acid of theformula j wherein R CO has the meaning given above, orareactivefunctional derivative of such acid witha nuclear substitutedaminopyridine of the formula I HzN R:

2;arn ino-5;carbamylrpyridine.,-

heating lower ani i esters such as the methyl or ethyl esterofltheacidspf Formula IIand also theamides with compounds of Formula HI, thecorresponding, substituted amides of Formula'I are obtained. Othersuitable reactive functional derivatives of acids of Formula II are thehalides and anhydrides, particularly the anhydrides mixed with carbonicacid semi esters. These functional derivatives are-reacted witha-compound of Formula III, preferably in the presence of an acid bindingagent, e.g. a strong tertiary organic base suchas' triethyl'amine,pyridine or -s-collidine, which can also serve in excess as reactionmedium, or they a refre'a'ctedin the presence of an excess of'thereactiomcornponent of Formula In in the presence or absence of an',inert organic solvent such as benzene, tetrahydrofuran or dimethylformamide.

Examples of alkylaminopyridines, of Formula III are 2-amino fichloropyridine, 3-amino-6-fluoro-pyridine, Z-amino-S-iodo-pyridine,2-amino-5-bromo-pyridine, 3-amino-6-chloropyridine,3-amino-6-methyl-pyridine; 2-amino-5-methyl-pyridine,2-amino-S-ethyl-pyridine, 2:,amino-5-nrpropyl-pyridine, I2-amino-S-isopropyl-pyridine, 3-amino-6-propionyl-pyridine,3-amino-6-methoxy-pyridine, 3-amino-fi-ethoxy-pyridine, 3amino-6-allyloxy-pyridine, 3-amino-6-methylmercapto-pyridine,3-amino-G-ethyhnercapto-pyridine, 3-amino-6-allylmercapto-pyridine,3-.amino-6-acetylamino-pyridine, 2-amino-5-methoxycarbonyl-pyridine,2-amino-5-ethoxycarbonyl-pyridine,2-amino-5-isopropoxycarbonyl-pyridine, and

As modificationof the reaction -of-acid halides with 'cbtnpounds'of-Formula III in the presence of acid binding agents, the reaction can bementioned of the acid halides 'with suitable tertiary organic bases,particularly triethylamine, in an inert organic solvent, removal byfiltration of the hydrochloride formed and reaction of the ketene orketene dimer present in the solution with the desired compound ofFormula'III. Reactive esters of acids of Formula II which can reactedwith-compounds of FormulaIlI in inert o'rganiesolvents, if necessarywith heating, are, e.g. theirp-nitrophenylesters and cy anomethylesters. The 1- imidazolides of the acids mentioned are reacted withcompounds of Formula III under similar conditions.

\ The'isocyanates and isothiocyanates derived from compounds of FormulaIII-are mentioned'as reactive functional derivatives of compounds ofFormula III which can be-reacted directly with acids of Formula II.These are'heated with the acids ofFormula H until the equimolaramount-of carbon dioxide'or carbon oxysulfide has been liberated. I

' 'Th'e'reactions'withisocy'an ates and isothiocyanates canbe'perforrned in the 'presence or absence of 'an' inert organicsolvent-having a sufiiciently highboiling point or range. Instead ofisocyanates, also "preliminary stages thereof can be usedflnparticularthe azides'of pyridine carboxylie'acids substituted corresponding to thedefinition for R can be r'ea'c'te'dwith acids of Formula II with heatingin suitableine'rt organic solvents. In addition, N-chlorocarbonylderivatives of compounds of Formula III, are reacted with 'sal ts,e.g.alltalijmetal salts, of acids of Formul a II'in the presence or absenceof inert organic solvents and the reaction mixtures are heated until theequimolar am unt ofc'arbon dioxide has been liberated from theoarboxylic acid-carbarnic acid anhydrides vfirst formed. other reactivefunctional derivatives of compounds of Formula HIare, eg. theN-trimethylsilyl derivatives of Another type of reactive derrvati ves ofcompounds of 'Formula III are the N, N- dipyridyl-carbodiimidessubstituted in both the pyridine rings corresponding to the definitionof R These are obtained, for example, by heating the corresponding,substituted N,N'-dipyridyl thioureas with lead (I I)-oxide in anhydroustoluene while gradually distilling off the solvent. On heating thesecarbodiimides with acids of Formula II in a stream of carbon dioxide attemperatures around 200, the amides desired of Formula I are obtained.

Instead of acids of Formula II'or their reactive functional derivatives,if desired the saturated bromine addition products of these acids or ofY reactive functional derivative thereof can be reacted with nuclearsubstituted aminopyridines or nuclear substituted alkylaminopyridines ofFormula III or with reactive functional derivatives thereof and theamides of polybromine fatty acids having 18 carbon atoms so obtained canbe debrominated in the known way. j t V The functional derivatives'ofboth 'reaction'co'mponents and also the reaction conditions for amideformation are substantially those given above for the direct productionof compounds of Formula I. Debromination is performed, for example, byboiling the intermediate products with zinc in ethanoL'As the bromineaddition products of acids of Formula I are often produced, e.g. inthe'case of linoleic acid and linolenic acid, during their isolationfrom natural mixtures of fatty acids and, after purification, again haveto be debrominated, the above modification of the process starting fromcrude acid mixtures necessitates no extra stepsin the reaction but isonly a change in the order of the steps, V t

if desired, compounds of Formula I produced by one of the processesgiven above, are converted-into another compounds of this formula. Inparticular, compounds of to 250 mg. of active substance butcorresponding amounts 6 tain the nitro group. The same is true of thecorresponding polybromine fatty acids amides.

=Daily dosages of amides of Formula I for the treatment of virusdiseasesand for inhibiting growth of tumors are, for mammalsabout 2 to100 mg. per kg. of body weight;

however, according to the high dosis tolerata maxima also higher dosesmaybe used. Within these margins the dosages for parenteraladministration are in general lower than those for oral administration.These daily dosages are advantageously administered in dosage unitscontaining 5 in forms no't'expressly suitable for single doses such assyitdlps, sprays, aerosols, powders and ointments can be us Dosage unitsfor oral administration preferably contain between 1% and 90% of anamide of Formula I or of a non-toxic salt thereof as active ingredient.They are produced by combining the active substance, for example, withsolid pulverulent carriers such as lactose, saccharose, sorbitol,mannitol; starches such as potato 1 starch, corn starch or amylopectin,also laminaria powder or citrus pulp powder; cellulose derivatives ofgelatines,

Formula I containing a nitro group as radical R are reduced, if desired,into corresponding compounds having an amino group as radical R The sameis also true of the corresponding, substituted polybromine fatty acidamides, i.e. the conversion of the nitro group into the amino groups canalso be introduced between the amide formation and the debrominat-ion inthe second process mentioned. The nitro group is reduced to the aminogroup, for example, by means ofhydrogenin' thepresence of a noble metalcatalyst such as, e.g. palladium on calcium carbonate, at roomtemperature and normal pressure in an organic solvent such as ethanol.The reduction is interrupted after about three times the molar amount ofhydrogen has been taken up.

Finally the amides of Formula I"containin"g 'anamino group as radical R'or the corresponding, substituted polybrom'ine fatty acid amides canbeacylated-to the corresponding amides containing an alkanoylamino group.The acylation is performed, for example, bytreatm'entwi-th a loweralkanoic acid halide or anhydride, if necessary inthe optionally withthe addition of lubricants such as magnesium or calcium stearate orpolyethylene glycols (Carbowaxes) of suitable molecular weights, to formtablets or drage cores. The latter are coated, for example withconcentrated sugar solutions which can also contain, e.g. gum arabic,talcum and/or titanium dioxide, or with a lacquer dissolved in easilyvolatile organic solvents or in mixtures of solvents. Dyestuffs can beadded to these coatings, for example, to distinguish between differentdosages of active substance.

Dosageunits for the rectal application are, e.g. sup- .positories whichconsist of a combination of an active substance or of a suitable saltthereof with a neutral fatty foundation or also gelatine rectal capsuleswhich contain a combination of the active substance or a suitable saltthereof with polyethylene glycols (Carbowaxes) of suitable molecularweight.

.Other forms for the treatment of virus infections of the air passagesare syrups and also aerosols and, for

. ceutically acceptable carriers, diluents and/or additives,

conventional for these purposes.

The following examples will serve to further illustrate the. productionof the compounds of the invention as well flOOml. of. benzene. 6 g.(0.02 mol) of linoleoyl chloride presence of an acid binding-agent suchas pyridine, or an be acylated of Formula I containing the amino groupas radical R are obtained in their turn, for example, by the reductionsof amides mentioned in the previous paragraph of Formula I which, in thecorresponding position, conas the production of pharmaceuticalapplication forms butshould not be construed as a limitation on thescope of the invention.

EXAMPLE 1 i N-(5-Chl0ro-2-pyridyl) -linolamide .2. 5.7.g.' (0.02 mol) ofZ-amino-S-chloropyridine and 2.22 g. (0.022 mol) of triethylamine aredissolved in (9,12-octadienoyl chloride), dissolved in 30 ml. ofhenzene, are added dropwise within 10 minutes while stirring and coolingwith ice water and the mixture is stirred for another 2 hours at roomtemperature. Precipitated tri- -ethylamine hydrochloride is separated bysuction filtration and washed with hot benzene; the washing is combinedwith thefiltrate.

-To -the;-filtrate which contains the desired N-(S-chloro-2-pyridyl)-linolamide, there are added as stabilizer 4 mg.

-of dodecylv gallate and 4 mg. of [D,L]-a-tocopherol,

benzene is then evaporated from the filtrate; the resulting oily crudeproduct (7.8 g.) is dissolved in low boiling petroleum ether (40-60")and chromatographed on alumina (activity III, according to Brockmann).

The alumina is eluted successively with petroleum ether (4060 petroleumether/ benzene and with benzene and the resulting fractions are testedby thin-layer chromatography (according to Stahl, silica gel G, solvent:acetone/hexane 1:4, development: phosphomolybdic acid 7 20% in alcohol,for the presence of N -,(-chloro-2-pyridyl)-linolamide (R, value: 0.7) IN The fractions containing pure N- (5-chloro-2-pyridyl)- linolamide arecombined and concentrated to an oil which slowly crystallizes at 20. Thecrystals havefa melting point of 28.

Fractions containing the impure product are combined, concentrated, andagain chromatographed (Alox III, 150 g)- The fractions containing pureN-(5-chloro-2-pyridyl)- linolamide which result from this secondchromatography are indentified as described above, combined" andconcentrated. p v

The following compounds are obtained inananalo'gous manner from thecorresponding starting materials:

- M.P.; degrees N-(6-fiuoro-3-pyridyl)-linolamide 30N-(5-iodo-2-pyridyl)-linolamide 51 N-(6-chloro-3-pyridyl)-linolamide Y48 N-(6-methyl-3-pyridyl)-linolamide 23N-(6-acetylamino-3-pyridyl)-1inolamide 128 The production of N-(6acetylamino-3-pyridyl)-linolamideis performed in tetrahydrofuran. Theproduct is recrystallized from ethanol.

EXAMPLE 2 N-(5-methyl-2- i 4.32 g. of (0.04 mol) of2-amino-S-methylpyridine. are dissolved in 100 ml. of benzene. 6.0 g.(0.02 mol) of linoleoyl chloride in 30 ml. of benzene are addeddropwisewithin minutes while stirring and cooling' ,(ice water) and the mixtureis stirred for another 2'hours at room temperature. Precipitated2-amino-5-methylpyridine hydrochloride is filtered off under suction andwashed with hot benzene. The washings are combined with the filtratewhich contains the desired product.

After addition of a stabilizer analogously to. Example 1 the filtrate isevaporated in vacuo and to the resulting crude product there are added50 g. of urea, dissolved in 150 ml. of hot methanol. The precipitatedcrystals of the urea adduct thus formed are filtered off under suction12 hours later, washed with 10 ml. of cold ether and recrystallized frommethanol. They are composed of 3 parts by weight of urea and 1.1 part byweight of N-(5-methy1- 2-pyridyl)-linolamide. In order to decompose thiscomplex, 10 g. of the urea adduct are added to-100 ml. of water. Theresulting oil vN -(S-methyl 2 pyridyl)-linolamide, is extracted withpetroleum ether. After evaporating the solvent in vacuo, there isobtained the purified N-(5-methyl-2-pyridyl)-linolamide, M.P. 16.

The crude N-(5-methyl-Z-pyridyl)-linolamide can also be purified bycentrifugal molecular distillation.

In an analogous manner is obtained: N-(6-methoxy-3- pyridyl)-linolamide,M.P. 28 via the respective urea ad- 1 ducts, the weight ratio of urea tothe respective being about 3:1.

EXAMPLE 3 N-(5-nitro-2-pyridyl)-linolarnidef 5.56 g. (0.04 mol) of2-amino-5-nitropyridine.are dissolved in 200 m1 of pyridine. 12 g. (0.04mol). oflinoleoyl chloride are added dropwise while stirring and-pooling(ice water) and the mixture is stirred for 6hoursat room temperature.The precipitated pyridine hydrochltuide .is filtered off under suctionand the pyridine is rem'ovedflin vacuo at 45 (11 Torr). The residue ispurified byfc olumnar chromatography analogously to Example I, M.P. 38The following compounds are obtained in -an analogous manner from thecorresponding starting materials 2.

linolamide N-(6-propoxy-3-pyridyl)-linolamide, M.P. 41,N-(6-ethoxy-3-pyridyl)-linolamide, M.P. 39,N-(5-bromo-2-pyridyl)-linolamide, M.P. 45N-(5-ethyl-2-pyridyl)-linolamide, 11 1.5169,N-(6-methylmercapto3-pyridyl)-linolamide, M.P. 48

8 N-(6-allylmercapto-3-pyridyl)elinolamide, M.P. 30,N=,(5fethoxycarbonyl-Z-pyridyl)-linolamide, M.P. 34.

EXAMPLE '4 N-(5-chloro-2-pyridyl)-linolenamide 2.57 g. (0.02 mol) of2-amino-5-chloropyridine and 2.22 g. (0.22 mol) of triethylamine aredissolved in ml. of benzene. 6 g. (0.02 mol) of linolenoyl chloride in30 ml. of benzene are added dropwise within 10 minutes, the-additionbeing made while stirring and cooling (ice water) in an atmosphere ofnitrogen, after which the mixture is stirred for 2 hours at roomtemperature. The reaction. product is worked up and purified analogouslyto Example 1. n 1.5251.

The following compounds can be produced in an analogous ma'nner fromthecorresponding starting materials:

N-(6-chloro-3-pyridyl)-linolenamide, M.P. 39, N- 5 -bromo-2-pyridyl)-linolenamide, M.P. 42 N-(5-iodo-2-pyridyl)-linolenamide, M.P. 52,

1I-( 6-methyl-2-pyridyl)-linolenamide, n 1.5236,N;(6-methyl-3-pyridyl)-linolenamide, M.P'. 28, N (6fluoro-3-pyridyl)-linolenamide, M.P. 28.

EXAMPLE 5 N-(S-methylQ-pyridyl)-linolenamide 4.32 g. (0.04 mol) of2-amino-5-methylpyridine are dissolved in 100 ml. of benzene, 6 g. (0.02mol) of linolenoyl chloride dissolved in 30 ml. of benzene are addeddropwise," the addition being made while stirring and cooling(ice'watef) in a stream of nitrogen. After stirring for 2 hours atroom'temperature, the reaction product is worked up and purifiedanalogously to Example 2. M.P. 31.

The following compounds are obtained in an analogous manner fromthe'corresponding starting materials: N-(6-methoxy-3-pyridyl)-linolenamide, M.P. 28.

N EXAMPLE. 6

g. i N-(5-nitro-2-pyridyl)-linolenamide EXAMPLE/7 v N-(S-mthyl-Z-pyridyl)-linolamide 4 (a) A solution of 8.24 g. (0.04 mol) ofN,N'-dicyclocarbo diimide in 50 ml. of tetrahydrofuran is addeddr'dpwisef'at 1 0 'to a solution of 11.2 g. (0.04 mol) oflinoleic'acidand 5.6 g. (0.04 mol) of p-nitrophenol in l0'0m l; of tetrahydrofuranwhile stirring. After stirring for 1' hour at j 10 and for 4 hours atroom temperature, the precipitated N,N' di cyclohexyl urea is filteredoff under suction and washed/with tetrahydrofuran and evaporated'in'vacuo'. The linoleic a'cid-p-nitrophenyl ester obtained m el tsa t 28.

'(b)' 4.01 g'."(0.01 molfof linoleic acid-p-nitrophenyl 'ester and10.8"g'; (0.1 mol) of 2-amino-5-methylpyridine are left to stand'in 50ml. ofchloroform for 4 days. After evaporating off the solvent, thecrude product is purified by columnar chromatography analogously toExample 1. The product is identical with'the N-(5-methyl-2-pyridy1)-linolamide produced according to Example 2.

EXAMPLE 8 A N-(5-amino 2-pyridyl) linolamide i 4.01 (0.0111 61 of N-(5nitro}2-pyridyl)-1inolamide for production see Example 6) are dissolvedin 150 ml. of purified ethanol, 1.5 g. of Pd-CaCO catalyst are added andthe whole is hydrogenated at room temperature and normal pressure untilv0.03 mol of hydrogen have been taken up (duration about 30 hours). Thesolution of the reaction product, after removal of the catalyst, isevaporated and the residue is recrystallized from methanol, M.P. 42. i

To prepare the hydrochloride of N-(5-amino-2-pyridyl)- linolamide thebase is dissolved in ethanol and an ethereal solution of hydrochloricaci clis added at The precipitate is filtered off and recrystallizedfrom ethanol-ether,

i EXAMPLE 9" N-(S-amino-Z-pyridyl)elinolenamide 4.01 g. (0.01 mol) ofN-(S-nitro-Z-pyridyl)-linolenamide (for production seeExample 9) aredissolved in 150 ml. of distilled purified ethanol, 1.5 g. of Pd-CaCOare added and the whole ishydrogenated for 30 hours at room temperatureand normal pressure. The reaction solution, after removal of thecatalyst is evaporated in vacuo and the residue is recrystallized frommethanol, M.P. 38"."

i EXAMPLE 10 I N-(-bromo-2-pyridyl)-linolamide 2.22 g. (0.022 mol) oftriethylamine are dissolved in 50 ml. of anhydrous ether. While stirringand cooling with ice water, 3 g. (0.01 mol) of linoleoyl chloridedissolved in 20 ml. of anhydrous ether are added dropwise within 5minutes. Then 1.73 g. (0.01 mol) of 2-amino-5- bromo-pyridine dissolvedin 50 ml. of ethyl acetate are added dropwise within minutes and themixture is stirred for another 2 hours.

The precipitated triethylamine hydrochloride is filtered oil undersuction and washed with hot benzene. N-(S- bromo-Z-pyridyl)-linolamideis obtained from the filtrate analogously to Example 1 by chromatographyon an alumina column, M.P. 45.

EXAMPLE 11 N-(5-bromo-2-pyridyl)-linolamide 2.79 g. (0.01 mol) oflinolamide and 1.75 g. (0.01 mol) of 2-amino-bromo-pyridine are heatedfor 2 hours at 220 while stirring in a stream of nitrogen. Aftercooling, the N-(S-bromo-Z-pyridyl)-linolamide is purified bychromatography on an alumina column analogously to Example 1, M.P. 45.

EXAMPLE l2 N-(5-caubamyl-2-pyridyl)-inolamide 6. 85 g. (0.05 mol) of6-amino-nicotine amide are dissolved in 100 ml. of dimethyl formamideand 5.05 g. (0.05 mol) of triethyl amine. While stirring and coolingwith ice water, 5.43 g. (0.05 mol) of trimethyl silyl chloride,dissolved in 30 mL of dimethyl formamide are added dropwise within '10minutes and the mixture is stirred for another 2 hours at roomtemperature. While stirring and cooling with ice water, 5.55 g. (0.055mol) of triethylamine and then 15.0 g. (0.05 mol) of linoleoyl chloride,dissolved in 30 ml. of dimethyl formamide, are added dropwise and themixture is stirred for another 2 hours.

The reaction mixture is poured into 800 ml. of ice water,

tested by thin layer chromatography (according to Stahl,

1 fractions containing pure N- (S-carbamyl-Z-pyridyl)-linolamide arecombined, evaporated in vacuo and the residue recrystallizedfrommethanol/ether, M.P. 1'42".

EXAMPLE '1-3 N-(S-niethyl-Z-pyridyl)-linolamide 1.62 g. of 1,'1-carbonyldiimidazole are added at room temperature to 2.80 g. (0.01 mol) oflinol'eic acid dissolved in 25 ml. of anhydrous tetrahydrofuran.

On completion of the carbon dioxide development, 1.06 g. (0.01 mol) ofZ-aminO-S-methyI-pyridine dissolved in 2-0 ml. of anhydroustetrahydrofuran are added and the reaction mixture is refluxed for 10minutes. The residue obtained on evaporating the tetrahydrofuran 01f invacuo is taken up in 50 ml. of ether and extracted with 50 m1. of water.The ethereal solution is concentrated and theN-(5-methyl-2-pyridyl)-linolamide is purified by chromatognaphy on analumina column analogously to Example 1, M.P. 16. 1 .-:-x-

; EXAMPLE 14 -N- (6-methyl-3-pyridyl)-linolamide' I "1.48 g. 0.01 mol)of 6'-methyl-nicotine azide and, 2.8 g.

(0.01 mol) of linoleic acid are dissolved in 10 m1. of xylene and thesolution is heated until nitrogen and car- :bon dioxide are developed.The heat is quickly removed and, as soon as the violent carbon dioxidedevelopment has subsided, the reaction mixture is refluxed.

0n evaporating off the solvent, the N-(6-methyl-3- pyridyD-linol'amideis purified by chromatography on an alumina column analogously toExample 1, M.P. 23.

EXAMPDE 15 N-'( S-acetylamino-Z-pyridyl) -linol amide 3.71 g. (0.01 mol)of N-(5-amino-2-pyridyl)-linolamide are left to stand for 12 hours atroom temperature in 10 ml. of pyridine and 10 ml. of acetanhydride. Thereaction product is poured onto g. of ice and the precipitated crystalsof N-(S-acetylamino 2 pyridyl)- linolamide are filtered off undersuction and recrystallized from methanol, M.P. 125.

EXAMPLE ll6 N-(S-amino-Z-pyridyl)-linolamide EXAMPLE 17 250 g. of activeingredient according to the invention, are mixed with 175.80 g. oflactose and 169.70 g. of potato starch. The mixture is moistened with analcoholic solution of 10 g. of stearic acid and granulated through asieve. A'fter drying, g. of potato starch, 200 g. of talcum, 2.5-0 g. ofmagnesium stearate and 32 g. of colioidal 'silicium dioxide are mixed inand the mixture is pressed into 10,000 tablets each weighing 100 mg. andcontaining 25 mg. of active substance (hydrochloride). If desired, thetablets can be grooved to attain better adaptation of the dosage.

EXAMPLE 18 A granulate is produced from 250 g. of active ingredientaccording to the invention. 175.90 g. of lactose and the alcoholicsolution of 10 g. of stearic acid. After wherein R OO--. represents thelinear acyl radical of an alkanoic ,acid, having 6-20-earbon atoms,alkenoie acid or alkapolyenoic acid, which linear 'acyl radical has from6 to 18 carbon'atoms, having 2 or 3 noncumulated C-C double bonds,

R represents hydrogen','"halog'en or lower alkyl, and 7 R representshydrogen-onlower alkyl.

2. A compound ofthe formula co-o-crn-o-x wherein X represent halogen, vV R CO- represents the linear acyl radical of an "alkanoic acid, having6-20 carbon atoms, allienoic acid or alkapolyenoic acid,whichf'linearaeyl radical has from 6 to 18 carbon atoms, having'2 or?noncumulated C-C double bonds, "R 'represents hydrogen, halogen or loweralkyl, and R represents hydrogen or lower alkyl.

3. A compound of the formula NOi wherein 'R CO represents the-linearaeyl radical of a fatty acid of from 18 to 20 carbon atoms andcontaining at least2 and at most '3' non-cumulated C-C double bonds, Rrepresents hydrogen halogen ,Ol'ylOWCI alkyl,- and R represents hydrogen,orlower alkyl. a

- V VI r ffrences Cited UNITED STATESrPAT 3,357,987 12/1967 Bucket 'a1."260-295 ALAN L. ROTMAN, Primary" Examiner U.s. c1. .R.

